Regular surveillance of over 200 members of 3 kindreds with familial medullary carcinoma (MCT) by annual provocative calcium infusion tests has provided a unique source of material for the study of this tumor's natural history on a continuing basis. A group of patients with small progressive increases in calcitonin response has been identified, and demonstrated C-cell hyperplasia by light and ultrastructural study. C-cell hyperplasia has also been reported in patients with prolonged hypercalcemia of diverse etiologies. The relationship of this type of C-cell proliferation to that seen in patients with familial MCT has not been clearly defined. Studies of C-cell distribution and ultrastructure in patients of both groups and MCT will be correlated with the results of calcitonin secretory studies. Utilizing the Long-Evans rat, a species with 43% incidence of spontaneous tumor by the age of 2 years, sequential studies of untreated animals will allow us to perform a comparative study defining the spectrum of C-cell growth abnormalities which precede the development of overt tumor, and to compare it with the histogenesis of the human tumor, and the C-cell changes in the hypercalcemic VX2 tumor rabbit model. Since the chronic administration of calcitonin secretagogues has been shown to serve as a stimulus for C-cell proliferation, an attempt will be made to accelerate the time course of the appearance of MCT in the rat by administration of these agents, and to analyze the cellular kinetics, morphology and function under these controlled conditions during the various phases of the proliferative response.